Hot-melt extrusion of modified release multi-particulates

ABSTRACT

The present invention includes compositions and methods of making a modified release pharmaceutical formulation and a method of preparation for the embedding of modified release multi-particulates into a polymeric or wax-like matrix. The modified release multi-particulates comprise an effective amount of a therapeutic compound having a known or desired drug-release profile. Modified release multi-particulates may include a polymeric coat or may be incorporated into particle or core material. The polymer matrix comprises a thermoplastic polymer or lipophilic carrier or a mixture thereof that softens or melts at elevated temperature and allows the distribution of the modified release multi-particulates in the polymer matrix during thermal processing. Formulation compounds and processing conditions are selected in a manner to preserve the controlled release characteristics and/or drug-protective properties of the original modified release multi-particulates.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims benefit of U.S. Provisional applications Ser.No. 61/090,439 and 61/107,027 filed on Aug. 20, 2008, and Oct. 21, 2008,respectively which are incorporated herein by reference in theirentirety.

TECHNICAL FIELD OF THE INVENTION

The present invention relates in general to the field of controlledrelease of active agents, and more particularly, to compositions andmethods for making hot-melt extrusions including modified releasemulti-particulates.

STATEMENT OF FEDERALLY FUNDED RESEARCH

None.

BACKGROUND OF THE INVENTION

Without limiting the scope of the invention, its background is describedin connection with the controlled release of active agents, e.g.,pharmaceutical agents.

One such patent is U.S. Pat. No. 6,335,033, issued to Oshlack, et al.for melt-extrusion of multiparticulates in which a unit dosesustained-release oral dosage form is taught containing a plurality ofmelt-extruded particles, each consisting essentially of atherapeutically active agent, one or more retardants, and optionalwater-insoluble binders. The particles have a length of from about 0.1to about 12 mm and can be of varying diameters and each unit doseprovides a release of therapeutically active agents over at least about8 hours. Methods of preparing the unit doses as well as extrusionprocesses and methods of treatment are also disclosed. However, therelease profile is determined by the type of melt-extrusion.Furthermore, the melt-extrusion process fails to address the need forthe release of drugs that are in fragile multiparticulates. The drugrelease in this patent is governed by the properties of thethermoplastic carrier polymer and not by the particles.

Yet another patent is U.S. Pat. No. 6,743,442, issued to Oshlack, et al.for melt-extruded orally administrable opioid formulations. Briefly, abioavailable sustained release oral opioid analgesic dosage form isdescribed comprising a plurality of multiparticulates produced via meltextrusion techniques. This patent claims a sustained-releasepharmaceutical formulation comprising an extruded blend of atherapeutically active agent, one or more hydrophobic materials selectedfrom the group consisting of alkylcelluloses, acrylic polymers, andmixtures thereof; and one or more hydrophobic fusible carriers having amelting point from about 30° to about 200 ° C. and selected from thegroup consisting of natural or synthetic waxes, fatty acids, fattyalcohols, and mixtures thereof, the extruded blend divided into a unitdose containing an effective amount of the therapeutically active agentto render a desired therapeutic effect and providing a sustained-releaseof the therapeutically active agent for a time period of from about 8 toabout 24 hours, the extruded blend being formed by mixing thetherapeutically active agent, the one or more hydrophobic materials, andthe one or more hydrophobic fusible carriers in an extruder to form theblend and extruding the blend through the extruder. Again, the releaseprofile is determined by the type of melt-extrusion and it fails toaddress the need for the release of drugs that are in fragilemultiparticulates. Again, the drug release in this patent is governed bythe properties of the thermoplastic carrier polymer and not by theparticles.

One approach as disclosed in patent application WO 2008/101743 (Gryczke2008) involves the blending of an anionic polymer exhibiting a low glasstransition temperature but too high permeability (Eudragit FS) with awater-insoluble polymer (Eudragit RS, RL or NE) to reduce the release inacid.

SUMMARY OF THE INVENTION

This invention provides compositions and methods for their preparationby embedding modified release multi-particulates in a matrix underpreservation of the dissolution characteristics of the original modifiedrelease multi-particulates. The present invention combines the benefitsof a monolithic dosage form that releases multiple unit dosage systemsafter administration. It has been found that the present inventionovercomes some or all of the problems that occur with alternativemethods that may be used to formulate modified releasemulti-particulates into monolithic systems such as compression intotablets or filling into capsules. These shortcomings include one or moreof the following: (1) problems of content uniformity of the finalproduct, especially but not only at low loading levels; (2) changes inthe drug dissolution profile of the final product compared to theunprocessed multi-particulates due to interference with releasecontrolling principles such as polymeric coating or matrices during theembedment process; (3) limited loading of the monolithic system withmulti-particulates due to the requirement of large amounts of excipientsto aid the embedment process or to protect the release characteristicsof the multi-particulates; (4) sensitivity of the final product tomoisture due to the permeability of the matrix-forming principle; and(5) possibility of tampering with the final product.

In one embodiment the present invention describes a controlled releasepharmaceutical formulation comprising one or more modified releasemulti-particulates having an effective amount of one or more therapeuticcompounds, wherein the multi-particulates comprise a known drug releaseprofile and are thermally processed into an extrudate in a thermoplasticpolymer matrix, a lipid material or both wherein the thermal processingconditions maintain the majority of the known drug release profile ofthe multi-particulates upon release from the thermoplastic polymermatrix or the lipid material.

The extrudate as described in the present invention comprises at least80% intact multi-particulates, wherein the multi-particulates comprise apolymeric film coat. In one aspect the controlled release pharmaceuticalformulation comprising multi-particulates with an inherent drug-releasecontrolling or a drug-protection principle comprises a polymeric matrixor a hydrophobic material. In another aspect the multi-particulatescomprise an enteric drug release coating. In yet another aspect themulti-particulates are coated for an extended release and moistureprotection of the one or more therapeutic compounds.

In another aspect the modified release multi-particulates are coatedwith an additional water-soluble or acid-soluble coat and are processedto minimize an incompatibility between the one or more therapeuticcompounds and one or more excipients present in the matrix. Thewater-soluble or acid-soluble coat comprises a polymer selected from thegroup consisting of polymethacrylates, cellulose derivatives,polysaccharides, proteins, or vinyl polymers. In other aspects themulti-particulates are film-coated drug granules, film-coateddrug-loaded pellets or film-coated drug-layered nonpareils. In specificaspects the multi-particulates are in a size range of 50-800 μm,preferably 300-500 μm and the polymeric film coat of themulti-particulates comprises between 10% to 60% polymer(s) (w/w), morepreferably 20-50%, based on an uncoated weight of themulti-particulates.

In another aspect the one or more polymers in the polymeric film coatare selected from the group consisting of polymethacrylates, cellulosederivatives, polysaccharides, proteins, or vinyl polymers, and may beplasticized. In yet another aspect the multi-particulates comprisebetween 5 to 80 weight percent of the one or more therapeutic compounds.In another aspect the thermoplastic polymer matrix comprises one or morecomponents that are at least partially crystalline polymers with amelting point below 80° C.

The thermoplastic polymers used in the present invention is selectedfrom the group consisting of poly(ethylene oxide)-polypropylene oxide)copolymer, poly(ethylene glycol) or poly(ethylene oxide) having amolecular weight less than about 1,000,000. In specific aspects theweight percent of the multi-particulates is 5 to 70 weight percent. Thepolymer matrix may dissolve, disintegrate or swell in dissolutionmedium, an aqueous medium to release the modified releasemulti-particulates or enable drug release from the multi-particulates bydiffusion.

The modified release multi-particulates of the present invention arefurther defined as comprising enteric polymers or water insolublemodified release polymers that control the drug release by diffusion orpH-dependent polymer dissolution. Delayed release articles may beprepared by processing modified release multi-particulates that areenterically coated, with less than 10% drug released in acidic mediafrom the dosage form comprising the enteric coated modified releasemulti-particulates, and when media is switched to a pH above 6.8,greater than 80% drug is released in 45 minutes in a buffer mediaoutlined in the U.S.P.

In one aspect the modified release multi-particulates further comprise aretardant matrix, wherein the retardant matrix erodes or disintegratesto release the modified release multi-particulates. In another aspectboth the matrix and the modified release multi-particulates arefilm-coated, matrix coated or both.

In another embodiment the present invention is a controlled releasepharmaceutical formulation comprising one or more modified releasemulti-particulates having an effective amount of one or more therapeuticcompounds, wherein the multi-particulates comprise a known drug releaseprofile and are thermally processed into an extrudate in a thermoplasticpolymer matrix, a lipid material or both, under thermal processingconditions that maintain integrity of the multi-particulates duringprocessing. The extrudate as described by the embodiment of the presentinvention comprises at least 80% intact multi-particulates.

In another embodiment the present invention discloses a controlledrelease pharmaceutical formulation comprising one or more modifiedrelease pellets with an average particle size of 300-3000 μm, whereinthe one or more modified release pellets comprise a pharmaceuticallyactive substance embedded in a matrix of one or more anionic polymersand a processing aid. In one aspect, less than 10% of thepharmaceutically active substance is released after 2 hours in asimulated gastric fluid pH 1.2 and at least 40% after 2 additional hoursin a pH 6.8 buffer or a pH 7.4 buffer. In another aspect more than 60%of the pharmaceutically active substance is released after 2 hours inthe pH 6.8 buffer or the pH 7.4 buffer.

In a specific aspect the average particle size of the one or moremodified release pellets is between 500 and 1000 μm. The particle sizeof the one or more modified release pellets as described by theembodiment of the present invention is 200, 300, 400, 500, 600, 750,800, 1000, 1500, 2000, 2500, 3000 and 5000 μm.

In one aspect a weight percentage of the pharmaceutically activesubstance is between 0.1-70%. In another aspect the weight percentage ofthe pharmaceutically active substance is between 5-40%. In yet anotheraspect the weight percentage of the pharmaceutically active substance is0.1, 0.5, 1, 2, 3, 4, 5, 10, 20, 30, 40, 50, 60, 70, and 80%. The one ormore anionic polymers is a copolymer of methacrylate and methacrylicacid, wherein the one or more anionic polymers are selected from thegroup consisting of acrylic acid, methyacrylic acid, vinyl acetic acid,crotonic acid, allylacetic acid, 4-methyl-4 pentonic acid, vinylsulfonate, styrene sulfonate and acrylamido methyl propane sulfonicacid. The copolymer contains at least 20% methacrylic acid.

In one aspect the one or more modified release pellets can withstand aload of at least 10N without undergoing a fracture or a deformation. Inanother aspect the one or more modified release pellets are transferredto a monolithic system comprising a tablet, a capsule or anycombinations thereof.

In one embodiment the present invention describes a method of preparinga controlled release pharmaceutical formulation comprising the step ofmixing one or more modified release multi-particulates comprising aneffective amount of a therapeutic compound having a known drug releaseprofile with a thermoplastic polymer matrix or hydrophilic waxcontaining matrix by thermal processing under conditions that preserve adrug-release controlling, a drug-protection characteristic or both ofthe multi-particulates. In one aspect the thermal processing isperformed by a hot-melt extrusion, conducted with a single-screw or atwin screw extruder at temperatures of less than about 100° C.

In another aspect the multi-particulates comprise a film coat that isapplied by a dry coating process, an aqueous coating process or by asolvent coating process. In yet another aspect the multi-particulatesare coated in a fluidized bed-coater. Sustained releasemultiparticulates may be obtained by coating with at least one ofhydrophobic polymers, hydrophilic polymers, gums, protein derivedmaterials, waxes, shellac, oils and mixtures thereof.

In another embodiment the present invention describes a pharmaceuticalsolid dosage form providing a controlled release of the therapeuticcompound and comprising the pharmaceutical formulation preparedaccording to the method of the present invention. In one aspect thepreferred site of administration of the composition described in thepresent invention is an oral route. In another aspect the controlledrelease is further defined as immediate, extended or delayed release.

In yet another embodiment the present invention discloses a method ofpreparing a controlled release pharmaceutical formulation comprising oneor more modified release cylindrical pellets comprising the steps of:(i) mixing a pharmaceutically active substance, one or more anionicpolymers, and a processing aid to form a mixture, (ii) processing themixture with a hot-melt extrusion process to form one or more extrudedstrands, and (iii) cutting the extruded strand to form the one or moremodified release cylindrical pellets. The method as described in theembodiment of the present invention further comprises the steps ofapplying a polymeric film coat to the one or more modified releasecylindrical pellets and spheronizing the one or more modified releasecylindrical pellets.

In one aspect the temperature during the hot-melt extrusion process doesnot exceed 200° C. In another aspect the temperature of at least one ofthe heating zones during the hot-melt extrusion process exceeds a glasstransition temperature of the polymer by at least 10° C.

In one embodiment the present invention is a method for determining oneor more extrusion parameters for preparing a controlled releasepharmaceutical formulation comprising: selecting one or more modifiedrelease multi-particulates with an effective amount of one or moretherapeutic compounds having a known drug-release profile, mixing theone or more modified release multi-particulates with a thermoplasticpolymer matrix or hydrophilic wax containing matrix, extruding themulti-particulates with the thermoplastic polymer matrix or thehydrophilic wax containing matrix under varying conditions to form anextrudate, determining a drug release profile for the extrudate, andselecting the thermoplastic polymer matrix or the hydrophilic waxcontaining matrix and the extruding conditions in which at least 80% ofthe one or more modified release multi-particulates maintain the knowndrug release profile.

BRIEF DESCRIPTION OF THE DRAWINGS

For a more complete understanding of the features and advantages of thepresent invention, reference is now made to the detailed description ofthe invention along with the accompanying figures and in which:

FIG. 1 shows a cross-section of an exemplary embodiment of a hot-meltextruded composition as provided by the invention;

FIG. 2 is a graph of drug release profiles for compositions preparedaccording to Examples 2, 4 and 7 and tested according to Example 9;

FIG. 3 is a graph of drug release profiles for compositions preparedaccording to Examples 2, 4 and 7 and tested according to Example 9. Thepellet load in the matrix was 30%;

FIG. 4 shows the drug release after 2 hours in medium pH 1.2 fordifferent multi-particulates according to Examples 1-4 and testedaccording to Example 9 before extrusion and after extrusion of 30%multi-particulates in Poloxamer 407 according to Example 7;

FIG. 5 is a graph of drug release profiles for compositions preparedwith 30% granules as defined in Example 1 and coated according toExample 4 after processing according to Example 7 in Poloxamer 407 orExample 8 when tested according to Example 9; and

FIG. 6 is a graph of drug release profiles for a composition preparedwith 30% granules as defined in Example 1 and coated according toExample 4 after processing according to Example 7 in Poloxamer 407 whentested according to Example 9 immediately after preparation and after 1year of storage at room temperature (22±1° C.) and ambient relativehumidity.

DETAILED DESCRIPTION OF THE INVENTION

While the making and using of various embodiments of the presentinvention are discussed in detail below, it should be appreciated thatthe present invention provides many applicable inventive concepts thatcan be embodied in a wide variety of specific contexts. The specificembodiments discussed herein are merely illustrative of specific ways tomake and use the invention and do not delimit the scope of theinvention.

To facilitate the understanding of this invention, a number of terms aredefined below. Terms defined herein have meanings as commonly understoodby a person of ordinary skill in the areas relevant to the presentinvention. Terms such as “a”, “an” and “the” are not intended to referto only a singular entity, but include the general class of which aspecific example may be used for illustration. The terminology herein isused to describe specific embodiments of the invention, but their usagedoes not delimit the invention, except as outlined in the claims.

The present invention includes compositions and methods of making amodified release pharmaceutical formulation and a method of preparationfor the embedding of modified release multi-particulates into apolymeric or wax-like matrix. The polymer matrix comprises athermoplastic polymer or lipophilic carrier or a mixture thereof thatsoftens or melts at elevated temperature and allows the distribution ofthe modified release multi-particulates in the polymer matrix duringthermal processing.

The present invention further details a formulation and method ofpreparation for pellets having a mean particle size of 300-3000 μm,comprising a pharmaceutically active substance in a matrix comprising ananionic polymer and one or more plasticizers. The pellets provide a drugrelease of less than 10% in simulated gastric fluid over 2 hours, andrelease at least 40% after another 2 hours in buffer of pH 6.8 and/or pH7.4.

The preparation of enteric pellets traditionally involves severalprocessing steps including wet-massing and extrusion, spheronization andfunctional coating. Theses methods require the use of organic or aqueoussolvents and time-and cost intensive drying procedures. The pelletsmanufactured according to these traditional methods usually exhibit lowmechanical strength and high friability. The process of hot-meltextrusion of the present invention allows the manufacture of entericmatrix pellets in a single step and continuous manner avoidingsubsequent film coating and abstaining from the use of organic solvents.A powder blend comprising the drug, an anionic polymer and optionalprocessing aids is mixed, melted and transported inside a heated barrelby one or two rotating screws before exiting through a product-shapingdie. Besides technological advantages, hot-melt extruded pellets allowthe incorporation of higher drug loadings under preservation of thecontrolled release properties which is attributed to the low porosity ofmelt-extruded matrices when compared to pellets prepared by traditionalwet-massing techniques¹. Melt-extruded pellets further exhibit lowfriability, high mechanical strength and enhanced robustness of therelease properties during downstream processing such as directcompression into single unit tablets².

The successful preparation of sustained release pellets by hot-meltextrusion has been reported in several publications³⁻⁵ and patents⁶⁻⁷.However, the manufacture of enteric pellets exhibiting a release of lessthan 10% after 2 hours in simulated gastric fluid remains challenging.Attributed to the larger surface area of small pellets, drug release inacid will be increased when compared to tablets as previouslydemonstrated for melt extruded Eudragit L100-55 matrices containing 20%drug⁸. Another aggravating circumstance to overcome is the opposingtrend between polymer permeability and processibility. Anionic polymerswith low glass transition temperatures and low melt viscosities producepellets that are too permeable in acid and release more than 10% of thedrug content. On the other hand, polymers exhibiting low permeabilityand good protection in acid are difficult to process by hot-meltextrusion due to their high glass transition temperature and high meltviscosity.

Dosage forms comprising multi-particulates provide advantages overmonolithic dosage forms. These advantages comprise improved distributionalong the GI tract and the potential of enhanced bioavailability andmore constant blood plasma levels, the avoidance of high local andpossible toxic drug concentration, a reduced risk of dose dumping, adecreased susceptibility of the drug absorption to food effects orphysiological factors, faster and less variable pharmacological effectsdue to more reproducible gastric transit times and expanded formulationflexibility by mixing of particles providing different actives orrelease rates. Post processing of multi-particulates is necessary toprovide the patient with a conveniently administrable dosage form.Monolithic systems such as tablets or capsules may be used as the finaldosage form and such solid compositions offer advantages over liquidformulations regarding storage stability, safety and patient compliance.

The two most common techniques include the filling of multi-particulatesinto capsules or the compression into tablets. The applicability of bothprocedures is compromised due to numerous short-comings. Capsules aremore cost-intensive than tablets and may be less secure due to theirhigher susceptibility to tampering. Capsule shells are hydroscopic andprovide little protection to light, oxygen and moisture. They aredifficult to open and consequently provide less flexibility in dosingoptions.

Tabletting involves the exposure of the multi-particulates to highunidirectional compaction forces that may cause coat rupture and/orparticle deformation and fracture. It has been reported that a strongparticle core is necessary to prevent cracking of Surelease E-7-7050 andMethocel A4C coats applied to Theophylline-comprising pellets⁹. Theapplication of a film coat did not change the strength of the drugpellet, regardless of the coat thickness. The core of themulti-particulates fractured before the coat broke, and was followed bycoat rupture when the crushed core was deformed under the compressionload. Beckert and coworkers reported an enhanced release of bisacodylfrom enteric coated pellets in acidic media when soft pellets with lowcrushing strength were used as opposed to hard pellets².

Sufficient rupture strength of the coat is further necessary to resistfilm damage at low degrees of particle deformation. Therefore, brittlepolymers do not qualify for the application as coating materials unlesshigh coating levels are used. Alternatively, high amounts of plasticizermust be added to increase the film flexibility during compression, butthese substances may leach from the product during storage. Theflexibility of Eudragit L30D-55 films can further be improved by mixingit with Eudragit NE 30 D, but the drug release during the buffer stagemight fail to comply with the USP requirements¹⁰. Films made withEudragit L30D-55, only, were too brittle to resist compression induceddamage despite plasticization with TEC and relatively high coating level(25%). Pellets coated with Kollicoat 30D MAE 30 DP alone lost theirenteric properties after compression because of the brittle character ofthis polymer, but a mixture of Kollicoat 30D MAE 30 DP and Kollicoat EMM30D provided sufficient protection in acidic media¹¹. Altaf andcoworkers reduced the fracture of Aquacoat ECD-30 coats by spray coatingthe pellet with an additional PEO layer¹². The swellable polymerhydrated during dissolution and was postulated to act as a sealant forcracks formed in the coat during compression.

The addition of cushioning agents such as wax/starch beads prepared bymelt pelletization at a concentration of 50% w/w in the final tablet wasdemonstrated to reduce damage of diltiazem hydrochloride pellets coatedwith Eudragit NE 30D¹³. A similar strategy was applied by Debunne andcolleagues to retain the dissolution characteristics of coated piroxicampellets after compression¹⁴. Enteric pellets coated only withplasticized Eudragit L30D 55 provided sufficient gastric protection over2 hours, but the amount of waxy pellets was required to exceed the loadof functional pellets¹⁵. Furthermore, the preparation of thesecushioning particles is labor and cost intensive and may interfere withthe disintegration of the tablet. The utilization of granules with highporosity as tabletting excipient for pellets was also shown to reducethe formation of indentions into the pellet surface, but could notprevent deformation by flattening of surfaces during compression¹⁶. Theefficiency of tabletting additives to act as cushioning agents isfurther limited by their particle size. A study conducted by Yao et al.with ethylcellulose coated theophylline powder demonstrated thattabletting excipients with smaller particle size were superior toprotect the film from damage attributed to their efficient cushioningability during compression¹⁷.

As detailed above, particle deformation under compression causes ruptureof functional films. Film cracking is a function of particle loading inthe tablet and limits the applicability of compression methods for highloadings of multi-particulates. It has been reported that up toapproximately 30% w/w particle loading-only multi-particulates at thesurface are affected by deformation and hence film damage¹⁰. Higherloading amounts will result in additional particle deformation in theinterior of the tablets because the hard particle surfaces are incontact with each other. The disintegration into the individualmulti-particulates will further be inhibited by particle fusion duringcompression. This phenomenon also limits the applicability of highparticle loadings.

Tabletting of multi-particulates is further challenging due todifferences in particle size, particle shape and true density betweenthe particles and the tabletting additives. The content uniformity ofthe final dosage form may be compromised by blend segregation and poorpowder flow during tabletting. Different strategies have been employedto overcome shortcomings concerning content uniformity such as coatingof the tabletting excipients directly onto the coated pellets¹⁸,processing of the tabletting excipients into placebo pellets of the samesize¹⁹ or utilizing fillers of small particle size²⁰. Most of thesesapproaches involve further preparation steps resulting in increasedoperating expenses. Beckert and coworkers investigated the influence ofthe pellet percentage in the tablet formulation on the contentuniformity²¹. The content uniformity was improved by increasing thepellet loading up to 70% and became independent of the filler particlesize due to the formation of a percolating cluster of pellets whichprevented segregation during compression. At this high loading level,the preparation of tablets became problematic and was only possible whenfillers with high binding capacity were utilized. However, tabletscontaining 10% w/w pellets exhibited high variations in drug content andfailed the USP requirements for content uniformity.

Alternatively, enteric pellets may be embedded into tablet-shaped plugsby alternate pouring of a molten carrier and the pellets into molds withcavities²². The reported process was manual, discontinuous and needed tobe interrupted to allow the carrier to solidify and prevent pelletsedimentation. The study was further limited to polyethylene glycol asthe carrier and a pellet load of 8-12% in the matrix.

Thermal processing in general, and hot-melt extrusion in particular,have been adopted from the plastics industry to manufacture matrixsystems for pharmaceutical purposes. The therapeutic compound is usuallyincluded as a powder or granules into the formulation and dispersed in amolten thermoplastic carrier such as waxes or polymers duringprocessing. The thermal processes involve elevated temperatures and theapplication of shear forces. Hot-melt extrusion is commonly utilized forthe preparation of solid dispersions of poorly soluble compounds.Depending on the solid state of the drug and the number ofdistinguishable phases in the extrusion product, solid solutions,amorphous mixtures or solid suspensions have been described in thescientific literature. In most cases, the drug particles undergoparticle size reduction, melting and/or dissolution in situ, resultingin modified properties of the active compound in the solid dispersionwhen compared to the bulk material. Amorphization, particle sizereduction and hydrophilic coating with the carrier material are the mostrelevant explanations for the increased dissolution profiles observedfor most solid dispersions. A patent filed by Miller, et al., disclosesa formulation and preparation method by hot-melt extrusion todisaggregate secondary agglomerates of crystalline or amorphouspre-manufactured drug particles and disperse the individual particles ina carrier under prevention of solid state changes or reaggregationduring processing or storage²³. Upon solidification, the material may beground into powders for post-processing or cut into tablets, mini-rodsor cylinders for post spheronization. Drug release kinetics iscontrolled mainly by the swelling and erosion kinetics of the carriermaterial, by the geometry of the dosage form and by the particle sizeand solid state of the active compound.

As a first step, the modified release multi-particulates comprising thetherapeutic compound are prepared. Next, these modified releasemulti-particulates are blended with one or more extrudable agents andare extruded, e.g., hot-melt extruded, into a final formulation in whichat least 50, 60, 70, 80, 90 or a higher percentage of the modifiedrelease multi-particulates release their active or therapeutic agentwith the same or equivalent release profile as before the extrusion uponrelease from the extrusion matrix. Alternatively, the drug release mayadditionally be controlled by the nature of the extruded matrix. Forexample, if the final formulation includes an extrudable matrix thatreleases the modified release multi-particulates after, e.g., traversingthe stomach, the release of the active ingredient will be controlled bythe matrix and by the properties of the modified releasemulti-particulates.

As used herein, the term “multi-particulates” refers to one or more unitdosage systems such as, but not limited to, pellets, beads, spheres,mini-tablets, seeds, spheroids or granules with modified drug releaseprofile. The multi-particulates comprise a drug-release controllingand/or drug-protecting film or matrix, such as a polymeric film ormatrix, whose intactness or efficiency is susceptible to certainconditions such as heat or mechanical forces that may occur duringpost-processing. The expression “core material” describes the nature ofthe interior part of multi-particulates that may also comprise afunctional coat. Exemplary “core-materials” may be pellets (sphericalmatrix systems that contain a drug and further excipients), granules(less spherical particles that are almost entirely composed of drug) ornonpareils (spherical particles without drug).

The terms “therapeutic compound”, “drug” and “active pharmaceuticalingredient” are used interchangeably to refer to chemical entities thatdisplay certain pharmacological effects in a body and are administeredfor such purpose.

Non-limiting examples of therapeutic compounds include, but are notlimited to, antibiotics, analgesics, vaccines, anticonvulsants;anti-diabetic agents, antifungal agents, antineoplastic agents,anti-parkinsonian agents, anti-rheumatic agents, appetite suppressants,biological response modifiers, cardiovascular agents, central nervoussystem stimulants, contraceptive agents, dietary supplements, vitamins,minerals, lipids, saccharides, metals, amino acids (and precursors),nucleic acids and precursors, contrast agents, diagnostic agents,dopamine receptor agonists, erectile dysfunction agents, fertilityagents, gastrointestinal agents, hormones, immunomodulators,antihypercalcemia agents, mast cell stabilizers, muscle relaxants,nutritional agents, ophthalmic agents, osteoporosis agents,psychotherapeutic agents, parasympathomimetic agents, parasympatholyticagents, respiratory agents, sedative hypnotic agents, skin and mucousmembrane agents, smoking cessation agents, steroids, sympatholyticagents, urinary tract agents, uterine relaxants, vaginal agents,vasodilator, anti-hypertensive, hyperthyroids, anti-hyperthyroids,anti-asthmatics and vertigo agents. In certain embodiments, the one ormore therapeutic compounds are water-soluble, poorly water-soluble drugor a drug with a low, medium or high melting point. The therapeuticcompounds may be provided with or without a stabilizing salt or salts.

As used herein, the term “friability” refers to the tendency for themulti-particulates or particles of the present invention todisintegrate, break, rupture or for coatings to rub-off or break-offfrom attrition during processing or handling. In the present invention,if such friability of the multi-particulates occurs, such particles willfail to provide the required therapeutic compound (or drug) release andthe dosage form will be unusable. The present invention provides asignificant advantage over the prior art because the thermal conditionsselected for the co-extrusion of the thermal matrix and themulti-particulates reduce or mostly eliminate the friability of themulti-particulates extruded into the extrusion matrix, thereby havingthe advantage of combining the release profiles of both the extrudedmatrix and the multi-particulate. In certain cases, the friability ofthe multi-particulate will be determined by the manner in which themulti-particulate was processed or formed, the manner in which themulti-particulates were coated or composition of the coating (if any).Accordingly, the composition of the coating (or shell), e.g., thepowder(s), shell(s), coating(s), binder(s), polymer(s) and orexcipient(s) are selected so that the finished product has at least amoderate amount of resistance to chipping, breakage, attrition,friction, and the like. Material selections for achieving this are knownin the art and are further described in the Examples.

Various methods of preparation may be used to manufacture the drugcontaining particles and high mechanical strengths are not necessary.Exemplary methods of preparation comprise wet-mass extrusion andspheronization, wet granulation and spray layering. Other methodsincluding hot melt extrusion, compression molding or similar thermalprocesses can be used.

A polymeric coat may be applied to the core material to modify the drugrelease and/or to separate the drug from its environment for protection.The coating level should be greater than 10% and, more preferably,greater than 20% w/w polymer weight gain, to ensure its stability duringthermal processing. The application of polymers with glass transitiontemperatures that are higher than the thermal processing temperature maybe necessary to prevent in-situ softening of the coat. However,optimization of the formulation will minimize the period of exposure ofthe multi-particulates to elevated temperature and render thisrequirement redundant. Optionally, an additional water-soluble or acidsoluble coat may be applied on top of the release-modifying coat to actas a barrier between the release-modifying coat and the carrier matrix.Non-limiting examples of polymers that may be included in the top coatare hydroxypropyl cellulose, hypromellose, hydroxyethyl cellulose,methylcellulose, carboxymethylcellulose sodium, dimethylaminoethylmethacrylate methylmethacrylate copolymer, chitosan, polyvinyl alcoholor polyvinylpyrrolidone.

All excipients and therapeutic compounds present in themulti-particulates should further exhibit sufficient thermal stabilityunder the applied temperatures.

Particle size requirements for the multi-particulates depend strongly onthe selected method and processing conditions and, in the case ofhot-melt extrusion, on the configuration of the extrusion equipment.Particles not exceeding about 800 μm with a preferred size range ofabout 300-500 μm are most suitable for processing by hot-melt extrusion.Single screw extruders may have certain advantages over twin-screwextruders, however, the goal is to preserve the original particlecharacteristics during thermal processing.

The carrier matrix comprises at least one thermoplastic polymer ormeltable lipid, and may also contain further functional excipients suchas disintegrants, glidants, plasticizers, antioxidants, retardants orother release-modifying agents, surfactants, stabilizing agents orprocessing aids. The term “matrix” relates to the material surroundingthe multi-particulates to provide a multi-particulate dosage form.

The term, “thermoplastic” when describing a polymer refers to one ormore polymers that melt and/or soften when heat is applied to allowmolding while maintaining good chemical stability. Exemplarythermoplastic polymers that may be used as matrix material include, butare not limited to, poly(ethylene oxide)-polypropylene oxide) copolymer,poly(ethylene glycol), poly(ethylene oxide), poly(vinyl alcohol),carbomer, polycarbophil, cellulosic derivatives, natural gums, povidone,poly(vinyl acetate), alginates, acrylic and methacrylic polymers. Lipidsinclude waxes such as beeswax, carnauba wax, glycerides (mono, di- andtri-), GMS, GMO, sucrose stearate. It is contemplated and within thescope of the invention that a combination of appropriate polymers and/orlipids may be used as matrix material in form of copolymers or physicalblends.

The multi-particulates may be blended with the carrier polymer prior toextrusion, or be dosed to the carrier during the extrusion process usinga separate port along the barrel. Feeding the multi-particulates over aport that is located in the vicinity of the die zone may reduce theexposure of the particles to thermal stress and shear forces and maypromote the physical and functional intactness of themulti-particulates.

Under the conditions of thermal processing, the multi-particulates mustremain generally physically intact so that the drug releasecharacteristics of the original particles are preserved in the matrixproduct. This is achieved by utilizing a carrier polymer that meets oneor more of the following requirements: Melting or softening atrelatively low temperatures so that the integrity of themulti-particulates is not compromised by thermally induced processessuch as softening, deformation, dissolution in the carrier polymer orchemical degradation whose likelihood increases as a function oftemperature. Low melt-viscosity to provide low resistance against therotation of the screw during hot-melt extrusion and to minimize theshear forces exerted on the multi-particulates. Good flowability in thesolid state and low melt-viscosity to facilitate rapid transit throughthe extruder barrel and reduce the residence time of the compositioninside the extruder barrel and hence the time of material exposure toelevated temperatures. Especially prill grades yield excellentflowability. Similarity with the multi-particulates regarding particlesize, spherical shape and true density to avoid blend segregation andensure content uniformity of the final product. A low degree ofintermolecular interaction with the excipients in the multi-particulatesthat get in direct contact with the thermoplastic carrier duringextrusion.

The resulting matrix system can be produced in strands, cylinders,tablets, hollow tubes or films. Post-processing may include variousproduct-shaping technologies such as pelletization or other cuttingtechniques, calendering, molding or spheronization to produce a dosageform of the desired geometry.

The final dosage form will exhibit properties that are comparable to theunprocessed multi-particulates in terms of controlled release of thedrug and/or its protection from environmental influences. As usedherein, the terms “modified release” and “controlled release” areinterchangeable and intended to describe immediate, extended or delayeddrug release profiles as used in the USP 31²⁴ and necessitates thepresence of a release controlling element. The release controllingelement may be a functional coat and/or may be provided by the matrixmaterial.

The present invention further discloses a formulation and a method ofpreparation for the hot-melt extrusion of enteric matrix pellets. Thepellets as described in the present invention have an average particlesize between 500 and 3000 μm, preferably between 500 and 1000 μm andcomprise a pharmaceutically active substance (drug) in a plasticized,anionic polymer matrix. The herein disclosed pellets release less than10% of the drug after 2 hours in simulated gastric fluid pH 1.2, andmore than 40% after an additional 2 hours in buffer pH 6.8 or 7.4,respectively. The herein disclosed pellets further exhibit highmechanical strength and low friability that makes them more suitable forpost-processing than pellets prepared by traditional methods. Examplesfor post-processing comprise functional film coating, directcompression, filling into capsules and melt extrusion into monolithicsystems.

Anionic polymers contain anionic groups that are protonated during theacidic stage, but ionize after pH increase. The anionic polymer that isused as the release controlling matrix is insoluble at low pH andexhibits a low permeability for the drug in the acidic stage ofdissolution testing. During the buffer stage, ionization of the acidicgroups of the polymer will increase the drug release by matrix swellingand/or erosion. Especially suitable are copolymers of methacrylate andmethacrylic acid of varying ratios (Eudragit S and Eudragit L) ormixtures thereof.

Pharmaceutically acceptable anionic polymers used for the melt extrusionprocess possess high glass transition temperatures and high meltviscosities at processing conditions. According to the invention,acceptable plasticizers or plasticizer mixtures are added to theformulation in sufficient amount to decrease the glass transitiontemperature and the melt viscosity of the polymer to avoid thermaldegradation as occurring at elevated processing temperatures. Acceptableplasticizers are non-toxic and regarded as safe, exhibit highplasticization efficiency for the anionic polymer and do not increasethe drug release above 10% during the acidic stage.

The pellets may comprise one or several pharmaceutically activesubstances at a combined level of about 0.1 to 70%, preferably 5 to 40%drug. The pellet formulation may further comprise additional excipientsand/or processing aids improving the chemical stability, processibilityor release properties of the pellets such as thermal lubricants,glidants and/or antioxidants.

The process of hot-melt extrusion of the present invention isadvantageous over traditional pellet preparation methods since it is aone-step, continuous process avoiding the use of solvents orlabor-intensive drying procedures. The components of the disclosedcomposition may be reduced in particle size and/or blended prior toextrusion utilizing commonly available milling and mixing equipment.Commonly used single or twin screw extruders of varying sizes and withone or several temperature zones may be used according to the invention.The temperature of at least one of the heating zones must be selected tobe at least 10, preferably at least 30° C. above the glass transitiontemperature of the plasticized polymer to produce a polymer melt ofsufficiently low melt viscosity. The extrusion temperature must furtherbe below the thermal degradation temperature of the polymer or of theother formulation components. The diameter and shape of the extrudedstrand is primarily governed by the diameter and geometry of the dieorifice, but may also be influenced by the viscoelastic properties ofthe polymeric melt. Circular dies with diameters between 500 and 1000 μmare preferred according to the present invention. The extruded strandsmay be cut into cylindrical pellets in the hot state or after cooling toroom temperature and may further be spheronized. Several technologieshave been developed for the subsequent pellitization and spheronizationin a continuous or semi-continuous manner²⁵⁻²⁷.

The terms “enteric dissolution testing” and “enteric drug release” areinterpreted as described in USP 31 chapter <711> for delayed-releasedosage forms²⁴.

The term “extended drug release” is used as described in USP chapter<711> for extended-release dosage forms²⁴.

EXAMPLE 1 Core Materials

TABLE 1 Examples for core materials that may be used for the preparationof modified release multi-particulates. (Moisture content determined asloss on drying of coated, cured particles after equilibration at 22 ± 1°C. and 50 ± 5% RH (n = 3).) Theophylline Moisture Core Material SupplierContent [%] Content [%] Drug Granules BASF 99.5 2.15 ± 0.13 PelletsSelf-made according 30.0 3.52 ± 0.08 to example 2 MCC Spheres AsahiKasei 10.8 3.50 ± 0.25 (Celphere ® CP-305)

EXAMPLE 2 Preparation of Pellets

The following procedure may be used to prepare pellets of the desiredparticle size. The drug and microcrystalline cellulose were placed in abowl and thoroughly premixed for 10 minutes. The PVP K25 was dissolvedin the water, and this binder solution is added dropwise to the powderunder stirring. The wet-massed material was then transferred into a LCIBenchtop granulator and extruded through a 0.6 mm screen at a rotationblade speed of 50 rpm. The extruded strands were placed in a CalevaModel 120 Spheronizer and rotated at 700 rpm for 3 minutes. The obtainedpellets were dried in a 40° oven for 24 hours and sieved. The fractionbetween 300 and 500 μm was used for subsequent enteric coating.

TABLE 2 Formulation for the preparation of pellets. Component Quantity[g] Percentage Anhydrous theophylline 90.0 30.0% Microcrystallinecellulose (PH101) 187.5 62.5% PVP K25 22.5 7.5% Water dest. 180.0

EXAMPLE 3 Drug Layering of Nonpareils

Active layered nonpareils of the desired particle size range wereprepared utilizing the following procedure.

TABLE 3 Coating dispersion for 30% drug weight gain of a 250 g batch.Component Quantity [g] Anhydrous theophylline 75.0 HPMC E3 (Pharmacoat603) 8.0 Talc 20.0 Water dest. 425.3

A 250 g batch of nonpareils made of 100% microcrystalline cellulose NFand having a particle size of 300-500 μm (Celphere® CP 305, Asahi KaseiAmerica, Inc.) were introduced in a Strea-1 fluidized bed coater(Aeromatic-Fielder) and layered with an aqueous dispersion ofTheophylline and HPMC E3 applying the following conditions:

TABLE 4 Process parameters for Strea-1 fluidized bed coater(Aeromatic-Fielder). Batch size 250 g Theoretical drug weight gain 30%Atomizing air pressure 1.5-1.8 bar Fan capacity 3-6 Nozzle diameter 1.0mm Inlet temperature 75-80° C. Outlet temperature 45-50° C. Spray rate2.0 g/min or 8.0 g/min * kg Spray mode bottom, Wurster column

The obtained layered particles were dried (24 hours in 40° C. oven) andsieved prior to enteric coating.

EXAMPLE 4 Enteric Coating of Core Material

The following formulation and processing method may be employed toprovide the core material (pellets, granules, nonpareils) with anenteric coat. Alternative functional polymers, plasticizers oranti-tacking agents may be used. The film coated particles may be driedovernight in a 40° C. oven or inside the coater, sieved and the 300-500μm particle size fraction may be used for subsequent hot-melt extrusion.

TABLE 5 Coating dispersion for 200 g batch. Formulation PercentageAmount [g] Eudragit ® L30D-55   12% polymer in dispersion 400 (120 gpolymer) TEC   10% based on polymer content 12 GMS  7.5% based onpolymer content 9 Tween 80   40% based on GMS 3.6 Water 575.4 Solidcontent 14.46%

TABLE 6 Process parameters for functional coating in a Strea-1 fluidizedbed coater (Aeromatic-Fielder). Weight gain 20-50% Inlet temperature36-38° C. Exhaust temperature 32-33° C. Nozzle diameter 1.0 mm Sprayrate 10 g/(min * kg) Set-up Wurster, bottom spray

Additional polymeric top coats may be applied to the enteric coatedmulti-particulates to improve their resistance to high temperaturesand/or shear forces during the subsequent hot-melt extrusion process.

EXAMPLE 5

Hot-Melt Extrusion of Enteric Matrix Pellets

The following formulations and procedure may be used to prepare entericmatrix pellets of the desired particle size. Powder blends for extrusionwere prepared by pre-mixing the polymer with the plasticizer andsubsequent blending with the drug using appropriate mixing equipment. Amini extruder equipped with two co-rotating screws and a circular 500 μmdie (Haake Minilab, Rheomax CTW5, Thermo Electron, Germany) may be usedfor the preparation of the drug loaded, polymeric strands, which werethen cut to obtain cylindrical pellets. The pellets may be spheronizedin a subsequent step employing appropriate spheronization equipment.

TABLE 7 Examples for the formulation of enteric matrix pellets.Plasticizer Eudragit ® Extrusion Amount S 100 Theophylline TemperaturePlasticizer [%] [%] [%] [° C.] none 0 70 30 220 TEC 10 60 30 180 TEC 2050 30 140 PEG 8000 10 60 30 180 PEG 8000 20 50 30 140 Methylparaben 1060 30 180 Methylparaben 20 50 30 140

EXAMPLE 6 In Vitro Method Drug Release Testing of Enteric Matrix Pellets

The drug release properties from the pellets may be determined asdescribed in USP 31, method <711> for delayed-release dosage formsmethod A. A paddle set-up (apparatus 2) was employed with a water bathto maintain the media temperature at 37±0.5° C. and the paddle speed setto 50 rpm. The formulations were placed in 750 ml simulated gastricfluid pH 1.2 (without pepsin, referred to as acid stage) for 2 hours andan aliquot of the fluid was withdrawn at the end of this period. Avolume of 250 ml 0.20 M tribasic sodium phosphate that had beenequilibrated to 37±0.5° C. was added after 2 hours to raise the pH ofthe media to 6.8 or 7.4, respectively (buffer stage). After expirationof the testing period, the remaining particles were completely destroyedby mixing with a high shear homogenizer to completely release residualdrug, an aliquot of the fluid was filtered and analyzed to determine thetotal amount released using a validated HPLC method. All average valueswere obtained from at least n=3 and were reported as % released from thetotal amount released.

TABLE 8 Drug release of melt extruded pellets (formulations according toinvention are in bold type). SGF Buffer Buffer Buffer Buffer BufferBuffer Formulation 2 hrs 45 min 2 hrs 4 hrs 6 hrs 8 hrs 10 hrs 10%Theophylline 27.2 81.3 98.8 75% HPMC AS LF 15% TEC 10% Theophylline 28.377.5 92.8 78.2% HPMC AS LF 11.8% PEO 200K 10% Theophylline 13.9 90.297.7 60% HPMC AS LF 15% Ethylcellulose 15% ATBC 10% Theophylline 22.297.2 99.5 75% HPMC AS HF 15% TEC 10% Theophylline 14.8 92.1 98.8 78.2%HPMC AS HF 11.8% ATBC 10% Theophylline 3.8 31.3 61.1 69.2% Eudragit L10020.8% TEC 10% Theophylline 4.2 35.9 68.0 95.0 69.2% Eudragit S100 20.8%TEC 10% Theophylline 6.1 47.0 83.5 99.9 64.3% Eudragit S100 25.7% TEC20% Theophylline 5.4 50.4 86.2 99.9 57.1% Eudragit S100 22.9% TEC 30%Theophylline 7.1 51.8 89.7 99.9 50% Eudragit S100 20% TEC 40%Theophylline 7.7 59.7 95.6 99.9 42.9% Eudragit S100 17.1% TEC 30%Theophylline 5.8 32.9 63.7 84.5 91.9 97.0 98.8 50% Eudragit S100 20%ATBC 30% Theophylline 83.2 90.7 99.4 50% Eudragit S100 20% PEG 8000 30%Theophylline 3.9 61.6 97.8 50% Eudragit S100 20% methylparaben 30%Theophylline 5.9 31.3 56.1 81.6 92.3 97.8 98.8 70% Eudragit S100 30%Theophylline 4.2 28.2 52.3 72.0 84.1 90.7 95.4 60% Eudragit S100 10% TEC30% Theophylline 18.2 41.3 72.4 90.5 97.3 98.5 99.2 60% Eudragit S10010% PEG 8000 30% Theophylline 5.7 36.7 60.9 81.5 90.5 96.4 98.2 60%Eudragit S100 10% methylparaben

EXAMPLE 7 Hot-Melt Extrusion of the Modified Release Multi-Particulates

The following is an example for the hot-melt extrusion of a monolithicmatrix with embedded enteric particles utilizing a RandcastleMicrotruder RCP-0750. Various carrier polymers may be used, and theloading of multi-particulates may be varied.

TABLE 9 Composition for the hot-melt extrusion of a multi-particulatematrix. Component Quantity [g] Modified Release Multi-particulates 30.0Carrier polymer 70.0

Multi-particulates and the polymer were blended in a V-shell blender oralternative blending device. The formulation exhibits excellent flowproperties and was fed through a hopper into the barrel by gravitationalforces only without additional force feeding. The separation of theblend components inside the hopper or extruder was reduced due to thespherical nature of the particles and similarities in particle size andtrue density. The following processing conditions are used for theemployed extruder. Variations in extrusion equipment, screw speed,temperature settings and motor load/torque are possible.

TABLE 10 Examples of carrier polymers and extrusion conditions using aRandcastle Microtruder RCP-0750. Melting Extrusion Temperature [° C.]Polymer Supplier & Grade Point [° C.] Zone 1 Zone 2 Zone 3 Die Poloxamer188 BASF, Lutrol F68 57.1 ± 0.3 40 45 47 47 NF Prill Poloxamer 407 BASF,Lutrol F127 58.9 ± 0.2 40 45 50 48 NF Prill Polyethylene Dow, Carbowax63.8 ± 0.3 40 45 50 50 glycol 4000 Sentry PEG 4000 Polyethylene Dow,Carbowax 64.3 ± 0.5 40 50 55 55 glycol 8000 Sentry PEG 8000Polyoxyethylene Dow, Sentry Polyox 69.7 ± 0.2 55 70 75 75 100K WSR N10Polyoxyethylene Dow, Sentry Polyox 69.9 ± 0.8 55 70 75 75 200K WSR N80

EXAMPLE 8 Direct Compression of Multi-Particulates

Functionally coated particles (30%), microcrystalline cellulose (Ceolus™KG-802, 65%) and superdisintegrant (Ac-Di-Sol®, 5%) may be directlycompressed into round tablets (333 mg, equivalent to 100 mg particles)using a single station manual Carver Press equipped with a concave, 10mm diameter die. The compression force was 5 kN and the tablet hardnesswas 17.1±1.6 kP.

EXAMPLE 9 In Vitro Method Drug Release Testing of EntericMulti-Particulates and Hot-Melt Extruded Matrices

The drug release properties from the particles or hot-melt extrudedmatrices may be determined as described in USP 31, method <711> fordelayed-release dosage forms method A. A paddle set-up (apparatus 2) wasemployed with a water bath to maintain the media temperature at 37±0.5°C. and the paddle speed set to 100 rpm. The formulations were placed in750 ml simulated gastric fluid pH 1.2 (without pepsin, referred to asacid stage) for 2 hours and an aliquot of the fluid was withdrawn at theend of this period. A volume of 250 ml 0.20 M tribasic sodium phosphatethat had been equilibrated to 37±0.5° C. was added after 2 hours toraise the pH of the media to 6.8 or 7.4, respectively (buffer stage).After expiration of the testing period, the remaining particles werecompletely destroyed by mixing with a high shear homogenizer tocompletely release residual drug, an aliquot of the fluid was filteredand analyzed to determine the total amount released using a validatedHPLC method. All average values were obtained from at least n=3 and werereported as % released from the total amount released.

The dissolution behavior of the multi-particulates before and afterextrusion into monolithic matrices is shown in FIGS. 2-5.

EXAMPLE 10 Determination of the Tensile Strength of Multi-Particulates

The mechanical strength of the core material, coated multi-particulatesand hot-melt extruded pellets was determined using a Chatillon UniversalTension/Compression tester model TCD-200. A flat circular steel platewas fitted onto a DFGS 50 digital force gauge and lowered in diametraldirection towards the an individual particle at a crosshead speed of 2.5mm/min. The load-deflection data was collected using Chatillon NexygenTCD force testing software. The mechanical strength was reported as thetensile strength and calculated using the following equation:

$\sigma = \frac{2P}{\pi \; {dl}}$

Specimens with diameters (d) equaling the length (l) were selected forthe experiments, and the maximum load (P) at which brittle fragmentationof the particles occurred was used for the calculations.

TABLE 11 Tensile strength of melt extruded Eudragit ® S100 pelletscontaining 30% theophylline as a function of plasticizer type and level.Diametral compression analysis of individual pellets (mean ± SD, n = 6).PEG 8000 Methylparaben TEC Tensile Plasticizer Tensile Strength ±Tensile Strength ± Strength ± Concentration SD [MPa] SD [MPa] SD [MPa] 0% 40.4 ± 5.2 40.4 ± 5.2 40.4 ± 5.2 10% 30.0 ± 3.0 27.0 ± 1.7 33.6 ±2.1 20% 29.5 ± 4.5 29.7 ± 2.4 17.4 ± 3.4

TABLE 12 Tensile strength of uncoated core material and coatedmulti-particulates. Diametral compression analysis of individual pellets(mean ± SD, n = 20). Before Coating After Coating Tensile Strength ±Tensile Strength ± SD [MPa] SD [MPa] Granules  7.3 ± 2.2  9.5 ± 2.8Pellets 21.5 ± 3.0 20.0 ± 3.4 MCC Spheres 33.6 ± 5.4 24.1 ± 4.5

It is contemplated that any embodiment discussed in this specificationcan be implemented with respect to any method, kit, reagent, orcomposition of the invention, and vice versa. Furthermore, compositionsof the invention can be used to achieve methods of the invention.

It will be understood that particular embodiments described herein areshown by way of illustration and not as limitations of the invention.The principal features of this invention can be employed in variousembodiments without departing from the scope of the invention. Thoseskilled in the art will recognize, or be able to ascertain using no morethan routine experimentation, numerous equivalents to the specificprocedures described herein. Such equivalents are considered to bewithin the scope of this invention and are covered by the claims.

All publications and patent applications mentioned in the specificationare indicative of the level of skill of those skilled in the art towhich this invention pertains. All publications and patent applicationsare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference.

The use of the word “a” or “an” when used in conjunction with the term“comprising” in the claims and/or the specification may mean “one,” butit is also consistent with the meaning of “one or more,” “at least one,”and “one or more than one.” The use of the term “or” in the claims isused to mean “and/or” unless explicitly indicated to refer toalternatives only or the alternatives are mutually exclusive, althoughthe disclosure supports a definition that refers to only alternativesand “and/or.” Throughout this application, the term “about” is used toindicate that a value includes the inherent variation of error for thedevice, the method being employed to determine the value, or thevariation that exists among the study subjects.

As used in this specification and claim(s), the words “comprising” (andany form of comprising, such as “comprise” and “comprises”), “having”(and any form of having, such as “have” and “has”), “including” (and anyform of including, such as “includes” and “include”) or “containing”(and any form of containing, such as “contains” and “contain”) areinclusive or open-ended and do not exclude additional, unrecitedelements or method steps.

The term “or combinations thereof” as used herein refers to allpermutations and combinations of the listed items preceding the term.For example, “A, B, C, or combinations thereof” is intended to includeat least one of: A, B, C, AB, AC, BC, or ABC, and if order is importantin a particular context, also BA, CA, CB, CBA, BCA, ACB, BAC, or CAB.Continuing with this example, expressly included are combinations thatcontain repeats of one or more item or term, such as BB, AAA, MB, BBC,AAABCCCC, CBBAAA, CABABB, and so forth. The skilled artisan willunderstand that typically there is no limit on the number of items orterms in any combination, unless otherwise apparent from the context.

All of the compositions and/or methods disclosed and claimed herein canbe made and executed without undue experimentation in light of thepresent disclosure. While the compositions and methods of this inventionhave been described in terms of preferred embodiments, it will beapparent to those of skill in the art that variations may be applied tothe compositions and/or methods and in the steps or in the sequence ofsteps of the method described herein without departing from the concept,spirit and scope of the invention. All such similar substitutes andmodifications apparent to those skilled in the art are deemed to bewithin the spirit, scope and concept of the invention as defined by theappended claims.

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1.-55. (canceled)
 56. A modified release pharmaceutical compositioncomprising an extruded thermoplastic polymer matrix comprised of apoly(ethylene oxide) or a poly(ethylene oxide)-polypropylene oxide)copolymer in which modified release multi-particulate pellets areuniformly disposed, wherein the modified release multi-particulatepellets have a particle size of from 300 to 800 μm or an averageparticle size of from 300 to 3000 μm, and further wherein individualmulti-particulate pellets comprise a modified release polymer matrix ora modified release polymer coating, and also further comprise aneffective amount of one or more therapeutic compounds.
 57. Thecomposition of claim 56, wherein the extruded thermoplastic polymermatrix comprises at least 80% intact multi-particulate pellets byweight.
 58. The composition of claim 56, wherein the extrudedthermoplastic polymer matrix is hydrophilic.
 59. The composition ofclaim 56, wherein a polymer of the extruded thermoplastic polymer matrixhas a molecular weight of less than 1,000,000.
 60. The composition ofclaim 56, wherein the multi-particulate pellets comprise 5 to 70 weightpercent of the composition.
 61. The composition of claim 56, wherein themulti-particulate pellets comprise an effective amount of 5 to 80 weightpercent of one or more therapeutic compounds.
 65. The composition ofclaim 56, wherein the modified release polymer is an enteric drugrelease polymer.
 66. The composition of claim 56, wherein themulti-particulate pellets comprise between 10% to 60% (w/w) of themodified release polymer.
 68. The composition of claim 56, wherein themulti-particulate pellets are film-coated drug granules, film-coateddrug-loaded pellets or film-coated drug-layered nonpareils.
 69. Thecomposition of claim 56, wherein the multi-particulate pellets, or acomponent thereof, does not dissolve in the extruded thermoplasticpolymer matrix.
 70. The composition of claim 65, wherein less than 10%of the one or more therapeutic compounds will be released in acidicmedia from the composition, and wherein 80% of the one or moretherapeutic compounds will be released in media pH above 6.8 accordingto USP 31, method 711 for delayed-release dosage forms method A.
 75. Thecomposition of claim 56, wherein the multi-particulate pellets have anaverage particle size of from 300 to 3000 μm.
 76. The composition ofclaim 75, wherein the multi-particulate pellets have a particle size offrom 300 to 800 μm and an average particle size of from about 300 to3000 μm.
 77. The composition of claim 56, wherein the multi-particulatepellets have a particle size of from 300 to 800 μm.
 78. The compositionof claim 56, further defined as a tablet.
 79. The composition of claim56, wherein the modified release polymer is further defined asimmediate, extended, sustained or delayed release polymer.